|Posted by australiandryeye on March 24, 2017 at 8:05 AM||comments (0)|
A first-in-class topical synthetic peptide being developed as a treatment for dry eye disease (Lacripep, TearSolutions Inc.) is set to enter into clinical development.
The novel proprietary agent, planned to enter a phase I/II trial in March 2017, is a fragment of lacritin, a naturally occurring, eye-selective tear glycoprotein. The agent was discovered in 2001 by Gordon W. Laurie, PhD, professor of cell biology and ophthalmology, University of Virginia, Charlottesville, and chief scientific officer and cofounder, TearSolutions Inc., Charlottesville, VA.
“Lacritin is largely released into tears by acinar cells of the lacrimal gland, although it is also produced by other cells, including those of the meibomian gland,” Dr. Laurie said.
Findings from laboratory and preclinical research have included collaborators from James Madison University; Eastern Virginia University; Cornell Univesity; University of California, San Francisco; University of Southern California; and University of Western Ontario.
Their research has found that the treatment topically stimulates basal tear secretion and wound healing, helps restore ocular surface cells to normal, and is deficient in the tears of persons with various kinds of dry eye disease.
“[The agent] has the same properties as the parent molecule, and unlike all existing therapies for dry eye disease, appears to address an underlying cause of the disorder rather than a downstream consequence,” Dr. Laurie explained. “Analogous to insulin treatment for diabetes, [lacritin] essentially represents a replacement therapy to correct an existing deficiency. For that reason, we believe it holds exciting promise as a very safe and effective therapy.”
The development history of the agent dates back to 1991 when Dr. Laurie was searching for a research topic at the University of Virginia.
“I was struck by the fact that no one seemed to be addressing the biological basis of dry eye disease other than downstream inflammation,” he added.
Dr. Laurie approached the National Eye Institute with his ideas. He submitted and received funding to biochemically screen for natural regulators of tear secretion.
“Trying to identify this natural tear stimulatory activity was like looking for a needle in a haystack,” he said. “The needle was the novel protein that we named lacritin.”
The first lacritin experiments showed it was released by lacrimal acinar cells and promoted tear secretion. In addition, lacritin was found to be important for the health and homeostasis of the ocular surface epithelium as evidenced by its ability to rescue cultured corneal epithelial cells stressed by exposure to inflammatory cytokines.
No other tear protein appears to share these properties because the capacity of healthy control tears to rescue inflamed cells was lost when tears were depleted of lacritin,” Dr. Laurie outlined. “Furthermore, tears from persons with dry eye lack lacritin and failed to promote health, but gained this benefit when spiked with lacritin.”
Mechanistic studies revealed mitochondrial function was restored. Lacritin was also found to transiently stimulate autophagy, the physiological process that maintains homeostasis by removing damaged proteins and cell organelles which accumulate when cells are stressed, such as by inflammation.
“By restoring a more normal ocular surface condition, lacritin appears to remove triggers that give rise to inflammation, thereby breaking the vicious cycle that perpetuates inflammation in dry eye disease,” Dr. Laurie said.
Results of preclinical studies in animal models showed lacritin was effective in promoting tear secretion, restoring ocular surface integrity, and reducing focal infiltration of inflammatory CD4+ T cells in lacrimal glands.
“In the animal studies, we found these benefits were achieved quickly and were persistent,” Dr. Laurie said.
In order to translate lacritin’s benefits into clinical use, the focus turned to creating a synthetic lacritin peptide which is smaller, easy to manufacture, and retains all of lacritin’s known activities. The final therapeutic agent consists of the lacritin C-terminal fragment.
Phase I/II trial plans
The first in-human study aims to enroll 201 patients with Sjögren’s syndrome dry eye. Patients will be randomly assigned into 3 groups to receive 1 of 2 doses of the lacritin agent or placebo for 4 weeks at a frequency of 3 times per day.
The initial clinical trial is focusing on Sjögren’s syndrome because clinical features are better defined in Sjögren’s dry eye compared with other forms of dry eye, Dr. Laurie said. Therefore, variability that commonly plagues dry eye studies will be reduced.
“We expect [the agent to] have benefit across the full spectrum of the condition because lacritin deficiency is apparent in all forms of dry eye,” Dr. Laurie added.
He also noted that although the therapy is administered 3 times daily in the first clinical trial, findings from preclinical studies suggest that once-a-day dosing may be feasible.
“We found that [lacritin] remained stable in rabbit tear film for 24 hours,” Dr. Laurie said. “Thus, it may have long acting activity.”
Safety is not expected to be a concern because no dose-limiting toxicity was observed in animals, he added.
“That is not surprising considering [the agent], like lacritin, is naturally occurring in human tears,” Dr. Laurie said.
Gordon W. Laurie, PhD
Dr. Laurie is co-founder and chief scientific officer of TearSolutions Inc. He is also an inventor on a number of issued and pending lacritin patents licensed by TearSolutions.
AXIM Biotech Retains Ora to Manage Upcoming Product Development and Clinical Trials on Glaucoma and Dry Eye Indications
|Posted by australiandryeye on March 21, 2017 at 11:50 PM||comments (1)|
NEW YORK, March 21, 2017 (GLOBE NEWSWIRE) -- AXIM® Biotechnologies, Inc. (AXIM® Biotech) (OTC:AXIM), a world leader in cannabinoid research and development, today announced that it has retained the services of Ora®, Inc., a global Contract Research Organization (“CRO”;), to perform the company’s upcoming product development (based on AXIM’s IP) and clinical trials for treating glaucoma and dry eye utilizing cannabinoid-based therapeutics. Ora is the world’s leading ophthalmology CRO for advancing products from pre-clinical through approval and post-market phases.
Ora will run the clinical programs under the supervision of Prof. Robert Ritch, Surgeon Director Emeritus and Chief of Glaucoma Services at New York Eye and Ear Infirmary of Mount Sinai School of Medicine in New York (NYEE). Prof. Ritch is a world-renowned expert in ophthalmology and glaucoma in particular, and has joined AXIM’s Advisory Board in December 2016.
“We are very pleased to team up with Ora, a world-class ophthalmology CRO, to guide our product development and clinical trials,” said George E. Anastassov, MD, DDS, MBA and Chief Executive Officer of AXIM Biotech. “Glaucoma and dry eye are highly prevalent ophthalmic diseases that require new and improved treatment options for patients. We look forward to working with Prof. Ritch and Ora in the development and clinically testing the efficacy of AXIM’s novel, proprietary, cannabinoid based solutions in treating glaucoma and dry eye and improving patients' well-being.”
“Despite new product approvals, glaucoma and dry eye remain ophthalmic diseases with significant unmet medical needs. Approximately 40% of glaucoma patients require more than one IOP-lowering medication. We hope that the development of new treatments with novel mechanisms of action will in turn reduce the risk of progression of visual field loss,” said David A. Hollander, MD, MBA, Chief Medical Officer of Ora. “Dry eye is one of the leading reasons for patient visits to eye care specialists. Novel therapies that address the signs and symptoms of dry eye disease will be welcomed by both dry eye sufferers and physicians.”
|Posted by australiandryeye on March 18, 2017 at 9:10 PM||comments (0)|
A University of Virginia Researcher has developed a formula that for the first time treats the causes, not just the symptoms, of dry eyes.
Millions of Americans suffer from dry eyes. To date, over-the counter drops don’t help much.
Gordon Laurie is a professor of cell biology at the University of Virginia and he says the prescription drugs treat only the inflammation, not the cause. He’s been working on this problem for 32 years, and says, he thinks he can fix it.
His drops go to clinical trials in March. If successful, Lacripep, the first drug to treat the cause of dry eyes, could be on the market in four years.
Listen to further audio with the Founder, Prof. Gordon Laurie here.
Clinical trial sites listed on TearSolutions: http://www.tearsolutions.com/Clinical_Trial_Sites.html
|Posted by australiandryeye on March 14, 2017 at 2:10 AM||comments (0)|
Based in Adelaide, Australia, she is Co-owner with Dr. Rene Malingre and is the principal optometrist at Alleve Eye Clinic that, at this point, is the only known stand-alone clinic in Australia exclusively treating dry eye patients. She hopes that establishing Alleve as a stand-alone clinic ensures that other optometrists “don’t feel threatened” to refer their clients, knowing that Dr. Rayner will refer them back for non-dry eye needs. At this point, the clinic is dedicated to dry eye twice a week but her objective is to transition it to a full-time dedicated clinic.
And there is certainly the need for such a clinic.
Read the full article here.
|Posted by australiandryeye on March 7, 2017 at 6:50 PM||comments (0)|
Written by Keaira Turner
Media contact: Alicia Rohan, [email protected]
University of Alabama at Birmingham School of Optometry researchers have been awarded a $1.9 million grant to study potential molecular markers in patients that could predict structural and functional changes of the eye in dry eye disease, and may lead to a targeted therapy.
“Dry eye is the most frequent eye disease that an eye care practitioner sees,” said Jason Nichols, O.D., Ph.D., professor in the UAB School of Optometry and assistant vice president for Industry Research Development in the UAB Office of the Vice President for Research and Economic Development. “The study will look at the lipid layer of the eye and the biochemical changes that cause dry eye. Once we understand these changes, we will be able to better treat the condition that affects up to 30 percent of the world.”
The National Eye Institute-funded study focuses on the impact of one of three layers on the eye, the outer lipid layer, an oil-based layer produced by glands that line the eye, sealing the tear film. The lipid layer helps decrease evaporation of our natural tears and provides a smooth surface needed for optimal vision. The lipid layer is where the problem lies for most people who develop dry eye symptoms.
Nichols was recently recognized as a top leader in the contact lens industry by Contact Lens Spectrum.
Nichols looks to target and identity the fatty acids that decrease the tear film, and their structural impact on the eye, using custom-built optical systems capable of measuring the very thin tear film. This study will help determine the functional impact of the lipid layer that increases the evaporation of the thinning tear film, causing dry eye.
“We hope to find the specific lipid that has been altered in the lipid layer to be able to provide patients with targeted treatment by either replacing the lipid or fixing the glands so they express the right amount of lipids,” Nichols said.
|Posted by australiandryeye on March 7, 2017 at 3:50 AM||comments (0)|
By David Bagdon, Publisher
Dry eyes are not a new phenomenon, in fact; most people have experienced them at various times throughout their lives. In most cases, dry eyes are a nuisance causing minor discomfort often brought about by eye strain or exposure to dry, windy conditions. However, for those suffering from chronic dry eye, the problem can cause significant pain and discomfort that can result in damage to the surface of the eye. It is estimated that over 25 million people in the United States and some 300 million worldwide suffer from dry eye.
Dr. Donald Korb of Korb and Associates, based in Boston, is widely recognized as one of the leading researchers and experts on the matter of chronic dry eye. Dr. Korb has been studying the issue for some 30 years and has published over 100 papers on the topic. As he explains, the issue first came to his attention in 1980 as he was researching and developing extended wear contact lenses.
To his surprise, several subjects in the study showed an unusual intolerance to this type of contact lens which led him to develop a hypothesis that the problem was tied to an oil deficiency on the surface of the eyes. While the accepted belief at that time was that dry eyes were the result of inadequate tear production, Dr. Korb was convinced that dry eye was due to an oil deficiency related to obstruction and dysfunction of the small Meibomian glands that line each eyelid.
When functioning correctly, the Meibomian glands serve to coat the ocular surface with oil to preserve moisture, while dysfunctional ones allow rapid evaporation and the resulting dryness. Dr. Korb teamed up with Dr. Antonio Henriquez of Barcelona, Spain, and the result was the discovery that the affected subjects in the study were suffering from obstructed Meibomian glands which resulted in the contact lens discomfort. Dr. Korb named the condition Meibomian gland dysfunction (MGD).
“What was difficult to believe is that a competent eye doctor could closely examine the eyes and the lids, yet would be unable to determine that the glands were obstructed without special tests utilizing pressure. In our original scientific article we stressed that the condition was not obvious. A thorough review of the non-obvious nature of Meibomian gland dysfunction was published in 2010. The difficulty in making this diagnosis led me to invent a device known as LipiView which is now used routinely to make this evaluation,” Dr. Korb said.
After identifying the problem, Dr. Korb directed his full focus to both research and the treatment of patients dealing with MGD. As he discovered, the Meibomian glands are small and delicate and if they are not producing quality oil, the problem can quickly deteriorate into acute inflammation. Due to his background as a researcher, Dr. Korb was able to rapidly study patient problems that arose in his own practice.
In order to diagnose and treat the problem of MGD on a much broader basis, he co-founded a company called TearScience which not only pioneered the LipiView tear evaluation device, but also produced LipiFlow, a device that simultaneously heats the inner lid surfaces while applying pulsatile pressure in order to improve oil flow and diminish inflammation. To date, the device is being used in over 250 eye care practices with over 100,000 patients having received treatment.
When asked about the significance of his invention, he looks back on that period as both challenging and rewarding.
“LipiFlow has been an exciting experience, perhaps the most exciting of my life. While I have over 20 inventions, 10 of which have been marketed, the complexity of developing the science of thermal pulsation treatment was by far the most complex. Although I have chosen not to be involved with the operation of the business, preferring research and clinical practice, seeing TearScience grow to employ over 100, including 10 engineers, has been like a dream,” he said.
“In addition, having had access to tens of millions of dollars for this research, we’ve had funding for many clinical studies and discoveries which are now in clinical practice to be used by all without fees,” he added. “This could not have been better or more exciting! I regularly receive letters from dry eye sufferers around the world who I have never met; that is a source of great gratification to me.”
Although Dr. Korb’s efforts have helped literally thousands of patients address their MGD and regain ocular comfort, he is concerned about the impact of electronic devices such as smart phones, tablets and computers on future generations. One issue that exacerbates MGD is extended screen time, not just from the standpoint of eye strain, but because it reduces one’s blink frequency, an action that is critical to the distribution of oil on the ocular surface.
According to Dr. Korb, our society’s dependence on electronic devices is likely to result in a dramatic increase in MGD over the coming years. In fact, he indicates he is already seeing an unusual increase in the number of cases involving young people and teens.
“Our group recently published a report in a prestigious journal titled ‘Dry eye is the wrong diagnosis for millions’. The correct diagnosis for over 80 percent of those suffering from dry eye is Meibomian gland dysfunction,” he said. “This is important for the future because the professions must recognize that obstruction of the glands is the usual cause of dry eye and that a key factor in this obstruction is inadequate blinking. It is well documented that excessive screen time dramatically reduces a person’s blink rate.
“In fact, a recent study conducted by our group showed that the incoming class at a prominent health care school already had concerning signs of dry eye. Based on the latter study, which will be published this year, 62 percent had symptoms which worsened as the day progressed, 41 percent were forced to use artificial tear supplements daily, 17 percent had discomfort using a computer, and over 50 percent had significant atrophy and permanent loss of at least 20 percent of their Meibomian glands. Dry eye is on its way to becoming a major public health problem and will only increase unless a government funded task force is enlisted to combat what is already a vocationally disabling disease for many.”
One of the most notable things about the way Dr. Korb addresses problems with dry eye is his very deliberate and methodical approach to diagnosis and treatment. Most likely a product of his background as a researcher, he methodically tests and reevaluates patients over a course of several appointments. In all cases he records copious notes about what is and isn’t improving. He’s quick to point out that dry eye is not something that can be resolved in a single visit. The ability of the eyes to maintain the appropriate amount of moisture depends on a delicate balance of Meibomian oil, adequate tears and proper blinking. Should these factors fall out of balance; the result can be inflammation which often cascades into problems resulting in even more discomfort.
“It is critical for the eye care practitioner to understand that a systematic approach is required to make the correct diagnosis before initiating treatment. While over 80 percent of all dry eye sufferers have meibomian obstruction and dysfunction, it is critical for the doctor to evaluate a minimum of four other factors; the nature of the blink, the efficacy of lid closure when sleeping, the extent of meibomian gland atrophy and the status of the sensory nerves,” Dr. Korb said. “One can treat with LipiFlow, but not achieve success for the patient unless all of these areas are addressed. The patient must understand that there will be homework, analogous to dental care, where office treatment must be supported by brushing and flossing.”
To colleagues and patients alike, Dr. Korb’s tireless work is fueled by a very rare level of passion and commitment. Whether he’s caring for patients or pursuing the next breakthrough in his research, Dr. Korb is a man on a mission. He is a deeply compassionate individual whose desire to learn about this affliction drives him to treat over 100 patients per month while still dedicating a minimum of three days per week to his research.'
When asked why he is so focused on this particular affliction and why he has made it his life’s mission, Dr. Korb is characteristically enthusiastic.
“Truthfully, some 35 years ago when I discovered the role of Meibomian gland dysfunction, I had plans to retire at an age which would allow me to follow my other interests, including working to help children pursue higher education in order to realize their own dreams. I also wanted to research the role of ego in mankind’s progress and failures – I still find this exciting.
“However, with every discovery, with every new publication, and with the creation of treatments, procedures and products for both patients and doctors, it was clear there was much more to accomplish. I still am excited every day by what I do and it is my hope that more can be accomplished to alleviate the suffering of over 30 million people in the USA with dry eye. Frankly, there is no area that provides me with the level of satisfaction and daily stimuli than what I do. I have been, and continue to be very fortunate.”
Korb and Associates is located at 400 Commonwealth Avenue in Boston. The office can be reached at 617-426-0370 or www.korbassociates.com.
|Posted by australiandryeye on March 7, 2017 at 3:45 AM||comments (0)|
An aging population, an ever increasing amount of time viewing digital devices and a growing trend in eye diseases are all factors expected to fuel a global increase in Dry Eye Disease. Currently, there are about 16 million people in the U.S. alone suffering from the condition, which is quickly becoming a common malady.
According to the research and consulting firm GlobalData, the global market for treating dry eye is expected to climb to an estimated $4.6 billion by 2024, more than doubling the estimated $2.2 billion market size of 2014.
Additionally, Dry Eye Disease has become associated with other conditions like glaucoma, rheumatoid arthritis, Sjogren's syndrome, post-LASIK surgery and patients taking anti-depressants, Dr. Penny Asbell, an ophthalmologist at the Mount Sinai Department of Ophthalmology in New York, said.
The condition causes a reduction of tears being produced needed to lubricate and nourish the front of the eye called the tear film. In a normal state, the layer provides the cornea and conjunctiva a healthy barrier from exposure as well as smoothing the anterior surface to provide the best optics for good vision. If the tear film becomes unhealthy and begins to break down symptoms of irritation as well as unstable and intermittently changing vision can happen.
Tear production tends to slow as people get older. By the time someone reaches 65 they can lose up to 65% of their tear volume compared to when they were 18. The condition can be exacerbated by medical conditions that begin to present themselves with age as well, by environmental influences like air pollution and windy, dry climates and by use of systemic medications.
Yet, it is not exclusive to seniors. Dr. Asbell said more cases are being reported in the young, most likely due to the increasing amount of time they spend looking at computer screens and digital devices that decreases the amount of blinking and lubrication of their eyes suffers.
Tears have a fairly intricate composition as they are made up of hundreds of different types of molecules, including natural antibiotics called lysozymes, vitamins, minerals, mucus, oil and water.
Dry Eye Disease is a persistent condition, much like chronic pain, that can interfere with quality of life due to constant dry, itchy, gritty feeling and red or swollen eyes. It is seen as a condition that is a multifactorial disease affected by inflammation, tissue degeneration and tear production deficit. It’s also one of the main reasons patients go to see an eye doctor.
Currently, there are only two FDA-approved treatments for Dry Eye Disease — Allergan’s Restasis and Shire’s Xiidra, which focus almost exclusively on suppressing inflammatory aspects of the disease.
Luxembourg-based Mitotech, which is a clinical stage biotechnology company focused on developing treatments for age-related disorders like Dry Eye Disease, recently received several U.S. patents covering various formulations of its lead compound SkQ1 and its use in ophthalmology.
“The interesting thing is that it’s a whole different mechanism improving cellular activity,” Dr. Asbell, who has had first-hand laboratory experience with SkQ1, said. “It’s totally different from Restasis and Xiidra. Both work as anti-inflammatory agents, but SkQ1 improves cellular function and has anti-oxidant effect.”
SkQ1 works on a cellular level by reducing damage caused by excessive reactive oxygen species (ROS), which are types of free radicals that play an important role in cell signaling. SkQ1 also selectively protects membrane’s cardiolipin from oxidation and by doing so prevents mitochondrial dysfunction and process of cell death called apoptosis. Another feature of the compound is that its oxidation chemistry allows it to be recycled in the mitochondria, creating a renewable antioxidant. The company has built its clinical development program to leverage SkQ1 across age-related disorders that could include treating neurodegenerative diseases like Parkinson’s and Alzheimer’s.
“SkQ1 was developed as an agent fighting a spectrum of age-related diseases at their root, which in our hypothesis is oxidative stress inside mitochondria,” Natalia Perekhvatova, Mitotech’s chief executive, said. “In case of Dry Eye Disease our ophthalmic solution Visomitin has been shown not only to suppress inflammation, but also to protect corneal and conjunctival cells from damage and to promote health of lacrimal glands, therefore addressing the disease from multiple angles.”
Mitotech’s program for the treatment of Dry Eye Disease is focused on Visomitin, which is approved in Russia and had a successful Phase II study in the U.S. that indicated statistically significant effect of SkQ1 on both signs and symptoms of dry eye.
The company is currently preparing Visomitin for Phase III trials, with a goal of getting the compound before the FDA by 2019.
“SkQ1’s innovation is that it is not a ‘me too’ drug,” Dr. Asbell said. “It’s a totally different way of addressing the problem of dry eye.”
|Posted by australiandryeye on March 4, 2017 at 1:35 AM||comments (0)|
Dry Eye Drug Development: When Will the Floodgates Open?
New therapies have the potential to turn the prescription market from a trickle to a deluge.
By René Luthe, Senior Associate Editor
Clinicians waiting for a new prescription drug for their long-suffering dry eye patients are going to have to wait a little longer. While many drug makers are on the case, their offerings will not be an option in the near future. Allergan's Restasis remains the only game in town in the way of prescription remedies. "The regulatory approval process for dry eye drugs is a nightmare," concedes EyeGate Pharma's president and chief executive officer, Stephen From.
What gives? Miami's William B. Trattler, MD, allows that part of the problem may be the FDA setting the bar too high. Yet the main problem, he believes, is dry eye's own peculiar nature. "Dry eye can be caused by aqueous deficiency or it can be due to poor tear film quality related to Meibomian gland dysfunction," Dr. Trattler notes. "Or, it can be a combination of these two forms of dry eye. Importantly, inflammation is present in both conditions."
However, not all the news is discouraging: Some drugs are inching closer to approval and researchers continue to gain valuable insights into the disease. Here's a snapshot of prescription dry eye remedies on the horizon.
More Obstacles Than Most
The combination of factors at work in dry eye disease is widely held to be the main reason for the lack of progress on the new-drug front. "The disease itself is highly variable," says Simon Chandler, PhD, director of clinical research at Ista Pharmaceuticals.
Eddy Anglade, MD, chief medical officer at Lux Biosciences, agrees. "There isn't a very good correlation between signs and symptoms," he says, "so trying to find that group of patients who have disease that will respond in a way that is convincing from a regulatory standpoint is challenging, given that the current regulatory approval standard is to demonstrate significance in a sign and in a symptom."
It has been so difficult to achieve, Mr. From points out, that no company has succeeded in getting a New Drug Application (NDA) filing approved. Where many drugs run aground, he says, is in trying to transition from phase 2 clinical trials to phase 3. "Most people worry about translating from animal models into humans," Mr. From explains. "In dry eye, we worry about phase 2 data translating into phase 3 — can somebody repeat a study a second time?"
Other experts familiar with FDA clinical trials and dry eye disease concur. Dry eye's variability means that when it is time for sponsors to scale their phase 2 trials to phase 3, the drug's efficacy may be harder to demonstrate. The disease's multifactorial nature also contributes to the difficulty in navigating the approval process. For each different cause, there is at least one way to potentially treat it. Matching the drug to the right kind of patient is crucial (see "Clinical Trial Pearls," below).
Part of the problem might reside with the regulatory process itself. The process for clearance of a new drug is complex and as the knowledge base concerning dry eye disease expands, the scientific basis for drug testing changes. According to Michael A. Lemp, MD, clinical professor at Georgetown and George Washington universities, "it was anticipated that the FDA would issue new guidelines for clinical trials in dry eye disease several years ago, but these have not been made public. The delay may rest with senior management within the Agency."
The result is that there is no "one-stop shopping" source where would-be sponsors can learn the guidelines for clinical trial endpoints. Instead, sponsors must go to the FDA and make a proposal as to how they would perform a clinical trial; the FDA reviews the proposal and informs the sponsor if it is acceptable, or which portions are acceptable or unacceptable.
"While the FDA is quite open to these inquires and willing to listen to novel ap proaches, many times companies new to this field feel as if they are guessing what the FDA wants," Dr. Lemp explains. "They wonder if the FDA has changed what is acceptable since the last time they heard. It's like trying to read the tea leaves."
Despite the regulatory hurdles, some dry eye drugs are making slow but steady progress toward beleaguered physicians and their patients. Most are anti-inflammatories, so their approval would fulfill a wish of Dr. Trattler's. "I use pulses of topical steroids frequently for dry eye patients, and if there were additional anti-inflammatory drugs that could work in this area, that would be very helpful for patients, since dry eye is an inflammatory condition."
• EGP-437. The closest drug to the goal is EyeGate's EGP-437. Currently in a phase 3 efficacy study, it's a dexamethasonederived corticosteroid solution delivered to the eye via an iontophoretic drug delivery system that enables the drug to overcome the problem of low bioavailability that limits other topical agents. "You have to try to bypass natural barriers that are in place: the tear film and cornea," Mr. From says. "It's very difficult to get a large quantity of drug into the front of the eye, or any drug to the posterior pole of the eye for retinal diseases." Iontophoresis also allows EGP-437 to bypass the method physicians have had to resort to deliver large quantities of drug into the eye: needles.
The doughnut-shaped applicator holds a sponge saturated with drug; the applicator is placed on the sclera after a topical anesthetic is applied to prevent the patient's blinking. An electrode at the base of the applicator is connected to a small, handheld generator that supplies a charge. A negatively charged drug in the foam portion gets a negative charge to the electrode, thus using the principle of electrorepulsion to push the drug at a high velocity into the eye.
The process, Mr. From says, requires only a couple of minutes. "Depending on how high the current is, or how long we leave this on the eye, will dictate how much drug goes into the eye and how deep it penetrates into the eye."
EGP-437 is a small molecule. In its recently-completed phase 2 study, it was able to treat multiple signs and symptoms of dry eye, rather than just one in each category, Mr. From says, "So we actually had the lucky advantage of being able to choose the best sign and the best symptom for our phase 3 trial." Even better, he says, was its onset of action, which begins within hours. "If you're a Sjögren's patient and you have severe dry eye, you are in a lot of discomfort and pain" and at risk for scarring, Mr. From explains. Such patients would welcome a therapy with rapid onset of action. "No other drug that I'm aware of works as quickly as our drug is working," he says.
Although data from EyeGate's 83-patient phase 2 trial are not yet available, the company did say that staining decreased in both fluorescein and lissamine green dyes, that conjunctival redness was reduced and that tear film breakup time increased.
As for dosage, the drug would be administered in a physician's office, probably on a quarterly basis, according to Mr. From, depending on severity. The company has begun enrolling patients for the phase 3 clinical trial of approximately 180 planned. Mr. From anticipates that the trial should be completed during the first quarter of 2011, with top-line data available at the end of that period.
He describes EyeGate's approach as acute therapy for a chronic problem. "We are able to put so much drug in so quickly to the tissues of the eye that we're knocking down the inflammatory cascade very rapidly. The drug doesn't stay in the eye very long, but the pharmacological effect lasts for a long time."
• CF101. Can-Fite BioPharma Ltd. recently opened an Investigational New Drug application (IND) with the FDA for a phase 3 study of its lead drug, CF101, for treatment of moderate to severe dry eye disease. Dr. Pnina Fishman, Can-Fite's CEO, says that CF101 exerts an anti-inflammatory effect and also an immunomodulatory one. The study will be initiated in few months.
An earlier phase 2 study, in which CF101 was taken orally as a monotherapy for 12 weeks, showed a statistically significant benefit in the clearing of fluorescein staining in the nasal, temporal, pupillary and inferior cornea, the company reports. CF101 also was found to be safe and well tolerated in the Phase 2. Further, the study showed a decrease in intraocular pressure in patients with dry eye, findings that have prompted Can-Fite to initiate a phase 2 clinical study for the drug's treatment of glaucoma.
The randomized, double-masked phase 3 trial will compare two oral doses of CF101 to placebo. Approximately 240 patients will be enrolled at multiple centers, to be treated for 24 weeks. The clinical endpoints are improvement of corneal fluorescein staining, tear production and dry eye symptom score.
• Low-dose bromfenac. Ista Pharmaceuticals' phase 2 trial of low-dose bromfenac (Remura) demonstrated improvement in both a key sign (lissamine green staining) and in symptoms (as measured by the Ocular Surface Disease Index) of dry eye in 38 patients over a six-week period. Further, patients treated with low-dose bromfenac maintained the improvement in signs and symptoms for 10 days after discontinuing treatment. The company is currently in the process of initiating the efficacy portion of the phase 3 program, which will entail two studies with a total of approximately 1,000 patients followed over a six-week period, according to Dr. Chandler. The safety portion of the phase 3 trial is tentatively scheduled to begin later this year and will comprise a six-month and a 12-month trial, with a total of approximately 4,000 patients.
Dr. Chandler notes that low-dose bromfenac could address the impact of inflammation on the ocular surface, a central feature of dry eye. "Controlling inflammation could both quiet the symptoms — that is, irritation, dryness, gritty, sandy feeling, burning in some cases — and improve the signs, such as staining, of ocular surface disease," he explains. The approach yields a dual benefit, Dr. Chandler contends, because of bromfenac's efficacy in dealing with pain as well as its ability to interrupt the inflammatory cycle, thereby allowing the ocular surface to heal. "There are very few medications that truly address the inflammatory cascade that is central to the disease while improving patient comfort," he says.
Although the inflammatory etiology of dry eye remains theoretical, Dr. Chandler says it does explain the results seen in the phase 2 open-label trial. Dr. Chandler contends that low-dose bromfenac has an onset of action that is "much faster" than the approximately eight weeks required for topical cyclosporine. In studies completed to date, he says, the drug produced a response rate that hovers around 70%.
Regarding safety, Dr. Chandler points out that higher-dose bromfenac studied in more than 1,600 patients did not result in any serious corneal adverse events; ocular adverse events observed in these studies resolved with no sequelae. From the perspective of global clinical experience with bromfenac, in about 19 million ophthalmic uses of the currently marketed higher concentration, there have been 22 serious corneal adverse events reported overall. Not all were considered drug related, Dr. Chandler points out, and most were in subjects who had undergone cataract surgery. "Lowering the concentration of bromfenac as we have done could further reduce the likelihood of severe corneal adverse events," he says. As part of its commitment to patient safety, Ista has incorporated frequent monitoring of the cornea into the protocols for the large safety trials being planned.
• SAR 1118. Sarcode Corp. says that the phase 2 results for SAR-118, a topical small-molecule lymphocyte function-associated antigen-1 antagonist, showed clear improvements in signs and symptoms of dry eye at 12 weeks. The trial was a randomized, multisite, doublemasked study involving 230 subjects. Various dose levels (0.1, 1.0 and 5.0%) were compared to placebo, with subjects receiving the drops BID for 12 weeks. The primary objective measure was inferior corneal staining; major secondary measures were OSDI symptom score and tear production by Schirmer test. The company will present full details of the phase 2 study in spring 2011. Sarcode is currently preparing for a phase 3 trial to begin in mid-2011.
• Mapracorat. Bausch + Lomb is addressing the issue of tear hyperosmolarity in dry eye disease, which research suggests is a mechanism involved in ocular surface inflammation, with its selective glucocorticoid receptor agonist (mapracorat), currently in phase 2 trials. In vitro studies suggest mapracorat inhibits hyperosmolar-induced cytokine release and mitogenactivated protein kinase pathways in human corneal epithelial cells. Development of the compound continues to progress as a novel product with a new mechanism of action for the treatment of dry eye, according to B+L.
A study in the September 2010 issue of Molecular Vision showed it to have comparable activity to dexamethasone in combating inflammation. The investigators evaluated mapracorat's anti-inflammatory effects in an in vitro osmotic stress model that induced hyperosmolar conditions in cultured human corneal cells. The model stimulated the release of pro-inflammatory cytokines interleukin-6, interleukin-8 and monocyte chemotactic protein-1, and also altered the phosphorylation state of p38 and c-Jun N-terminal kinase (JNK), and the transcriptional activity of NFkappaB and AP-1. The researchers found that the incubation of cells with mapracorat inhibited hyperosmolarinduced cytokine release with potency comparable to the dexamethasone control group. Additionally, increased phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat, and the compound caused a significant decrease in the hyperosmolar-induced rise in NFkappaB and AP-1 transcriptional activity.
• RX-10045. One of a class of medicines called resolvins, RX-10045 is a small-molecule lipid mediator that Resolvyx Pharmaceuticals says activates the body's own mechanisms for shutting off inflammation. It is administered as a topical eye drop. Resolvyx completed a phase 2 trial last year for chronic dry eye. In the randomized, placebo-controlled, 232-patient trial, RX-10045 produced dose-dependent, statistically significant improvement on the primary endpoints for both the signs and symptoms of dry eye, and was generally shown to be safe and well tolerated, the company says.
The phase 2 study examined three doses of RX-10045 and used a controlled adverse environment (CAE) simulator to measure corneal staining in a stressful drying environment, as well as daily patient diaries using a standard visual analog scale to assess symptom improvement over the course of the 28-day study. The drug produced a significant dosedependent improvement from baseline in symptoms recorded in daily patient diaries. It also reduced staining of the central cornea by 75% (P<0.00001) versus placebo, the difference approaching statistical significance (P=0.11). Additionally, the drug showed a significant improvement in CAE-induced staining in the inferior cornea and in the composite of central and inferior cornea, which also approached statistical significance over placebo (P=0.09).
Resolvyx says the phase 3 trial should begin by the end of the year.
• AzaSite. Currently there is no prescription product indicated for blepharitis, a void Inspire Pharmaceuticals would like to fill with AzaSite (azithromycin). The drug is already approved as a treatment for bacterial conjunctivitis, but it did not meet statistically significant endpoints in two phase 2 trials for anterior blepharitis last spring. Though a four-week trial did demonstrate improvement in measured signs and symptoms compared to placebo, statistical significance was not achieved for the primary endpoint of mean lid margin hyperemia.
On the secondary endpoints, however, Inspire president and chief executive officer Adrian Adams reports seeing some statistical significance in the areas of signs and symptoms. In the two-week trial, there were no statistically significant improvements for AzaSite compared to vehicle; this included the primary endpoint of clearing of lid debris.
The company says it will use the data obtained from these studies to continue to develop trial parameters using AzaSite as a treatment for both anterior and posterior blepharitis, and expects to refine the trial design through the end of this year. The refinement will include study populations and "seeking improved mappability for assessing and measuring signs and symptoms," says Mr. Adams. "With that, we are looking to utilize the photographic reading centers to maximize the trial."
Inspire anticipates completing the additional phase 2 AzaSite clinical work in 2011. The initiation of the phase 3 trial should begin sometime later next year.
• LX-214. Lux Biosciences' dose-ascending phase 1 trial showed that LX-214, a novel topical formulation of voclosporin, was well tolerated by healthy volunteers. There was no difference in tolerability between the vehicle control and the concentrations of drug tested (0.2% and 0.02%). In five subjects diagnosed with dry eye syndrome, the cohort "showed some improvement in their signs (measured by Schirmer's tear test) and symptoms (measured by the OSDI); most notably, the changes observed occurred in the relatively brief timeframe of the study, two weeks compared to what has been reported previously with cyclosporine emulsion," according to Dr. Anglade.
Voclosporin affects the immune response at the surface of the eye, he explains. "We think by controlling the local inflam matory response, it will allow the tear-producing lacrimal gland and the surface of the eye to heal and improve tear production.
LX-214 belongs to a class of agents known as calcineurin phosphatase inhibitors, developed by the company into a nanomicellar formulation. "This renders LX214, a highly insoluble compound, a solution as opposed to an emulsion," Dr. Anglade explains. He believes the drug's solution formulation will help make it better tolerated than cyclosporine emulsion.
Another advantage, says Dr. Anglade, is voclosporin's higher concentration. "A limitation of other forms of topical cyclosporine is that sufficiently high concentrations may not be achieved locally. The ability to achieve high local concentrations may translate into improved efficacy. We'll be able to assess that concept hopefully in the phase 3 when we do a large dose-ranging study."
Dr. Anglade adds that the company is planning a phase 2 proof-of-concept study for the near future.
• Restasis X. Allergan reports that it is currently testing a new variation of cyclosporine, Restasis X, in phase 2 clinical trials. The company is not able to speculate on expected timing for FDA approval.
In related news, in a study published in the August issue of the British Journal of Ophthalmology, researchers evaluated the efficacy and safety of two concentrations (0.05% and 0.1%) of cyclosporine A in aqueous solution compared to vehicle in treating the signs and symptoms of moderate-tosevere dry eye patients.1 At Day 21, the 1% group showed statistically significant improvement (p<0.05) in four symptoms and three ocular signs; the 0.05% showed statistically significant improvement in three symptoms and three signs; and the vehicle-only group in two symptoms and two signs. According to the researchers, at Day 42, the 0.1% group performed demonstrated improvement in four symptoms, while the 0.05% group demonstrated improvement in one symptom and one sign.
Hope for The Future
Dr. Lemp's vantage point as a participant in many FDA trials gives him reason to believe that the regulatory situation for dry eye drugs will soon improve. "As we learn more about the pathological processes at work in dry eye disease, new treatment strategies are emerging and data to support new endpoints are being published," he notes.
For one thing, in a meeting earlier this year, the FDA's Wiley Chambers, MD, expanded the criteria for primary endpoints that the agency will accept, including studies that document a correlation between signs and symptoms. Included in that slide was a list of inflammatory cytokines in the tears and tear osmolarity. "That's new," says Dr. Lemp. "That's potentially big."
Patient-reported outcomes are gaining favor with the FDA as well. The most common vehicle for reporting patient symptoms has been the 100-point scale OSDI. However, showing the required 29-point improvement in symptoms has been onerous. It has required sponsors to find patients who were highly symptomatic — "Who at least start out with 50 to 60 points on the scale," Dr. Lemp says. "And that rules out 90% of the population with dry eye."
New studies re-examining the relationships between subjective patient changes and levels of disease severity, novel ways to assess patient-reported improvement and a better understanding of the relationship between signs and symptoms in dry eye disease all have the potential to open the door to less onerous but scientifically rigorous study designs, Dr. Lemp notes. He believes that this augurs well for demonstration of clinical efficacy and the appearance of an expanded therapeutic portfolio of drugs for the more effective management of dry eye disease.
Perhaps the best reason to believe that the fortunes of prescription dry eye drugs will improve? "Let's put it this way, to my knowledge, there are probably more than 30 drugs in the pipeline," says Dr. Lemp. Many companies are investing in the dry eye market, and not just "the usual suspects" such as Alcon, Allergan and B+L.
The fact that Restasis could generate an approximate half a billion dollars in revenue last year despite its demonstrated effect in only about 15% of the patients studied (according to the package label), indicates significant unmet medical need and a healthy bottom line for those willing to invest.
With industry on board and the FDA willing to update its clinical trial criteria, the conditions for victories seem to be increasingly in place. OM
1. Baiza-Durán L, Medrano-Palafox J, Hernández-Quintela E, Lozano-Alcazar J, Alaníz-de la O JF. A comparative clinical trial of the efficacy of two different aqueous solutions of cyclosporine for the treatment of moderate-to-severe dry eye syndrome. Br J Ophthalmol. 2010 Aug 1. [Epub ahead of print]
|Posted by australiandryeye on March 2, 2017 at 7:55 PM||comments (0)|
Acthar – An New Drug for Eye Inflammation
The American Academy of Ophthalmology did not use the word inflammation in the official definition of Dry Eye until 2004. It took several years after that for Dry Eye to be called a disease instead of a syndrome. Naming is one thing and getting doctors to treat the disease in a new way is another. Then and now some doctors treat dry eye disease with artificial tears hoping that lubrication will help instead of treating the inflammation. I realized in 2000 that Dry Eye was due to inflammation and could be helped by anti-inflammatory treatments like cyclosporine drops and Intense Pulse Light. I encountered resistance to my treatment ideas but eventually eye doctors began seeing the benefits of anti-inflammatory treatments. More and more medications that have been used for systemic inflammation are finding a place in ocular inflammation. We have had a growing number of patients with chronic inflammatory conditions that are affecting the eye and more specifically the ocular surface. These patients have an allergic our autoimmune disease that is causing the glands that produce our tear to malfunction. Some medications have helped these patients like oral and topical steroids but the side effect profile is high. We are beginning a study using a different type of anti-inflammatory medication, Acthar.
For many people with chronic inflammation, ocular or otherwise, steroids are a way of life. Because their bodies are mistakenly attacking their own organs, steroids must be used to tamp down the response to avoid damage. In the eye, unchecked inflammation can lead to cataract, glaucoma, and even blindness.
Inflammation is different than infection. Inflammation means that the body’s natural defenses have been triggered by something (surgery, trauma, or an infection) and a cascade has begun of cells and chemicals in order to fight it. Inflammation alone does not require antibiotics. Infection generally implies that there is some agent (bacteria, parasite or virus) that is causing a problem and usually triggers inflammation as well. Antibiotics might be appropriate here.
Inflammation of the eye can occur at any level: keratiis, scleritis, retinitis and uveitis which can be anterior, posterior or in the middle (pars planitis). There are many diseases that can be associated with eye inflammation like multiple sclerosis, Crohn’s disease, irritable bowel and psoriasis.
Topical and oral steroids have been the mainstay of ocular inflammatory treatment for decades but keeping patients on them long-term is not ideal because of the many side effects that can occur like bone loss, gastric ulcers and fluid retention. Now, a drug that has long been approved for use in systemic inflammatory conditions like lupus, MR, sarcoid and rheumatoid arthritis is being used for severe allergy and other inflammatory eye conditions.
How does it work? Acthar contains the hormone ACTH (adrenocorticotropic hormone) which stimulates your own body to produce more natural steroid hormones so that patients can reduce or eliminate the need for additional steroids or other immunosuppressants like methotrexate or cyclosporine. Unlike steroids, Achthar uniquely binds to a specific receptor (melanocortin) to help down regulate both inflammation and the signals that keep inflammation going once started. These receptors are found on 5 different types of immune modulating cells throughout the body including T-helper and T-regulatory as well as macrophages and dendritic cells. Achthar is given as an in-home injection similar to insulin treatments once or twice week as needed.
Besides uveitis, Inflammation is at the root of many ocular diseases and conditions. Acthar is currently being studied for many inflammatory diseases including optic neuritis. Dry eye disease are also caused and perpetuated by inflammation. If you have moderate to severe dry eye and are looking for relief, Toyos Clinic is currently recruiting subjects for free treatment with Acthar to learn more about how this exciting new medication might help to relieve the signs and symptoms of dry eye.
|Posted by australiandryeye on March 2, 2017 at 4:05 AM||comments (0)|
Research shows we read emotions in each other’s eyes – that’s the power of eye language. But common symptoms of Chronic Dry Eye disease like red, itchy, burning eyes may be sending the wrong message, one you don’t intend.
Chronic Dry Eye (CDE) is a medical disease that, over time, can decrease the eye’s ability to make and/or maintain sufficient quality and quantity of tears for a healthy tear film. Up to 33 million people in the United States suffer from symptoms of CDE.
Visit www.eyepowerment.com for more information.
|Posted by No More Tears on July 19, 2016 at 10:15 PM||comments (1)|
What Causes Eye Pain?
Eye pain is an unpleasant sensory and emotional experience including sensory-discriminative, emotional, cognitive, and behavioral components and supported by distinct, interconnected peripheral and central nervous system elements. Normal or physiological pain results of the stimulation by noxious stimuli of sensory axons of trigeminal ganglion (TG) neurons innervating the eye. These are functionally heterogeneous. Mechano-nociceptors are only excited by noxious mechanical forces. Polymodal nociceptors also respond to heat, exogenous irritants, and endogenous inflammatory mediators, whereas cold thermoreceptors detect moderate temperature changes. Their distinct sensitivity to stimulating forces is determined by the expression of specific classes of ion channels: Piezo2 for mechanical forces, TRPV1 and TRPA1 for heat and chemical agents, and TRPM8 for cold. Pricking pain is evoked by mechano-nociceptors, while polymodal nociceptors are responsible of burning and stinging eye pain; sensations of dryness appear to be mainly evoked by cold thermoreceptors. Mediators released by local inflammation, increase the excitability of eye polymodal nociceptors causing their sensitization and the augmented pain sensations. During chronic inflammation, additional, long-lasting changes in the expression and function of stimulus-transducing and voltage-sensitive ion channels develop, thereby altering polymodal terminal's excitability and evoking chronic inflammatory pain. When trauma, infections, or metabolic processes directly damage eye nerve terminals, these display aberrant impulse firing due to an abnormal expression of transducing and excitability-modulating ion channels. This malfunction evokes 'neuropathic pain' which may also result from abnormal function of higher brain structures where ocular TG neurons project. Eye diseases or ocular surface surgery cause different levels of inflammation and/or nerve injury, which in turn activate sensory fibers of the eye in a variable degree. When inflammation dominates (allergic or actinic kerato-conjunctivitis), polymodal nociceptors are primarily stimulated and sensitized, causing pain. In uncomplicated photorefractive surgery and moderate dry eye, cold thermoreceptors appear to be mainly affected, evoking predominant sensations of unpleasant dryness.
|Posted by No More Tears on July 11, 2016 at 8:05 AM||comments (0)|
A look at neuropathic pain and its relationship to dry-eye diagnosis and therapeutic strategies.
When dry-eye symptoms include photophobia, it’s likely there’s an underlying neuropathic etiology.
We typically attribute dry-eye disease to a deficiency of lacrimal gland secretion, reduced meibomian gland function or some combination of these.1 For many, sufficient mitigation of symptoms can be achieved with tear augmentation.2 Others present with signs of surface desiccation and an autoimmune spectrum that is consistent with desiccating dry-eye disease such as that sometimes associated with Sjögren’s syndrome. But how do we explain patients who don’t show a correlation between tear deficiency or hyper-evaporation and chronic dry eye-like symptoms? In some cases, eyes that feel dry are not dry.3 What of those patients who report the perception of dry eye, with burning, irritation and even ocular pain that’s unresponsive to dry-eye management? In this article, we’ll attempt to unravel the mysteries associated with neuropathic pain and dry eye, and its implications in dry-eye diagnosis and treatment.
Dry Eye-Like Symptoms
Dry eye-like symptoms are triggered by specialized corneal nerve receptors4 designed to protect the integrity of the mirror-smooth corneal tear film necessary for enhancing the optical quality of the external corneal surface. This collection of nociceptors—mechanoreceptors, chemoreceptors and thermoreceptors—detects the subtlest changes in the ocular surface environment and functions as our cornea’s alarm system to warn us of potentially harmful disruption of the status quo. In particular, specialized thermal sensors provide an indirect measure of the thickness of the tear film. By sensing slight changes in ocular surface temperature, they monitor the rate of tear-film evaporation to provide a measure of both tear-film thickness and osmolarity in real time.5 The sensors’ responses to environmental conditions are a modulation of their excitability and an alteration of neuronal action potential firing rates. Like any such alarm system, modulation can be either positive or negative. As an example, on a windy day evaporation at the ocular surface is increased, and the activation of thermoceptors will increase the firing rate of the corneal sensory nerves, triggering an increase in lacrimal gland secretion to compensate for the accelerated tear-film thinning. Like all sensory nerves, continuous input modulates the set point, or activation threshold. All is well as long as this set point is in synchrony with other parts of the sensory feedback loop.
What happens when there is dysregulation of the sensory nerve circuit? If the triggering threshold is too high, the system will be relatively insensitive to the external environment, and the tear film will thin and break up, causing a loss of clarity, unstable vision and an exposed ocular surface. If the sensor threshold is set too low, the biological alarm will be triggered prematurely, generating dry eye-like symptoms in the presence of a normal tear film: a false alarm. These sensory circuits are described as being sensitized, and would be expected to require thicker-than-normal tear films to keep the dry-eye alarm in a silent mode. Under these conditions, sensory neurons respond to the ocular surface environment with symptoms of dryness, even though there is little or no stimulus generating that perception. Like all sensitive, powerful and complex systems, corneal innervation is vulnerable to component breakdown, with the result being neuropathic pain, a disease in its own right.
Dry Eye-Like Pain
Activation thresholds of tear film corneal sensors are lowered in the presence of inflammatory products such as pro-inflammatory cytokines.6 Increased activity of sensory nerves can also cause inflammation in the form of neuro-inflammation, which in turn ramps up the activity of pain-carrying nerves, leading to a self-perpetuating phenomenon known as peripheral sensitization.7 For many patients this can be reversed after resolution of the inciting stress and ocular surface inflammation.8 Some dry-eye patients experience only transient episodes of pain, whereas others have persistent symptoms of chronic disease. Neuropathic pain is by definition “pain arising as direct consequence of a lesion or disease affecting the somatosensory system,” and is often chronic.9
The transmission of dry-eye pain signals to the somatosensory cortex is not a passive process. Along the way, these electrical signals are modified by feed-forward and feedback systems that typically intensify the signals. This explains the unique property of pain to become amplified during a constant noxious stimulus, in contrast to most other types of sensory responses that adapt during persistent stimulation and thereby attenuate the responses. This physiological phenomenon, known as central sensitization, occurs with dry eye-like pain as well.8 Since the trigeminal brainstem was shown in animal models to be the location of central control of homeostatic corneal wetness,10 corneal algesia11 and aversive responses to light,12 the brainstem may also be the origin of the clinical expression of dry-eye-related pain. The possibility that disorders of the dry-eye alarm system itself can explain the variety of clinical patterns associated with dry eye-like pain offers a strikingly different perspective. Moreover, the location and persistence of this dysfunctional alarm system can alter the functional anatomy through the well-known, innately powerful neuroplasticity of the central nervous system. These maladaptive changes in the CNS result in neuropathic pain.
Possible Origins of the Pain
For us to be able to manage these cases effectively, it’s important to recognize the factors influencing neuropathic pain. Age-related dry-eye disease is characterized by the attrition of corneal nerve fibers. Its consequences are associated with an increased sensitivity to tear evaporation, or corneal evaporative hyperalgesia. Pain fiber attrition also occurs in de-afferentation hypersensitivity, a phenomenon found in the skin of healthy elderly subjects. The loss of nerve fibers in these conditions is associated with increased activity of the surviving nerves.13 The parallels between this condition and age-related dry eye are striking.
In mice, it has been demonstrated that sensory nerve injuries, such as those caused by LASIK axotomies, trigger a phenotypic change in the somata of the surviving nerves from conduction to regeneration, promoting the expression of atopic pain generators that are hypersensitive and hyper-responsive14 and that are transported to the regenerating nerve sprouts and the central terminals of severed axons from the nerve somata in the trigeminal ganglion where they’re expressed. This likely is responsible for the complaints of dry-eye symptoms following refractive procedures. Persistence of the regenerating phenotype long after healing has occurred, sometimes years after LASIK, as suggested by the characteristic morphology of regenerating nerves and increased numbers of mature dendritic cells in the sub-basal plexus, may explain the chronicity of dry-eye pain even in the absence of external signs of inflammation.
Even in the absence of a surgical trigger, normal afferent signals generated by tear evaporation could be augmented and distorted during their passage through a malfunctioning trigeminal brainstem. In this way, dry-eye symptoms can be experienced in certain diseases characterized by central sensory processing issues, such as fibromyalgia, with symptoms mimicking dry eye in the absence of overt signs.15
It has been well known for years that our psychological well-being profoundly influences our immunological status. Pain thresholds are also known to be increased by meditation.16 The flip side of this should not be a surprise. In the present context, patients with depression or post-traumatic stress disorder have a twofold increased risk of a dry-eye diagnosis compared to those without these diagnoses. Studies with Asian populations have shown similar relationships between depression and dry eye. Data from the national Veterans Administration database demonstrated that patients with chronic pain diagnoses are more likely to also have a dry-eye diagnosis. Patients with dry eye were also found to have higher pain sensitivity at a remote site (forearm) than those without the disease.8
We see that neuropathic pain accompanying dry eye might also be born from central sensitization in the central nervous system, and this possibility should be considered when weighing the contribution of signs versus symptoms presented by our patients diagnosed with dry-eye disease.
Continue reading here: http://www.reviewofophthalmology.com/article/neuropathic-pain-the-artifice-of-dry-eye
|Posted by No More Tears on July 11, 2016 at 4:40 AM||comments (0)|
Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome."
A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized.
We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain.
Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome."
© 2015 American Academy of Pain Medicine.
|Posted by No More Tears on July 6, 2016 at 9:20 PM||comments (0)|
Oculocin Propo Testimonial
Oculocin Propo provides a natural, preservative free option for supporting and treating the ocular surface. I have achieved outstanding results with patients suffering from chronic dry eye, where they feel their eyes are more comfortable, lubricated and ‘relieved’. Furthermore, I have also been able to correlate these results with improved tear film quality and surface staining during examination. This is another effective tool that should be considered in the complex battle against ocular surface disease.
– Shonit Jagmohan, Optometrist BOptom (Hons), Ophthalmic Medicines Prescriber, Orthokeratologist
Member of the Public
My children are constantly getting conjunctivitis &my doctor has prescribed various antibiotics which seem to work for a short while, then the conjunctivitis reoccurs.
Finally I discovered a natural eye drop that treats conjunctivitis and I am pleased to say, this has worked on my children and ever since I have used, it has cleared up the conjunctivitis
Thanks goodness I discovered Oculocin Propo.
I recommend you try it if either you or a family member suffers from conjunctivitis
Kim Sbisa-Victoria Australia
SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study
|Posted by No More Tears on July 6, 2016 at 5:10 AM||comments (0)|
This Phase 2 clinical trial assessed the efficacy and safety of the novel antioxidative, renewable compound SkQ1 for topical treatment of dry eye signs and symptoms.
In a single-center, randomized, double-masked, placebo-controlled, 29-day study, 91 subjects with mild to moderate dry eye instilled the study drug twice daily and recorded dry eye symptoms daily. Subjects were randomized 1:1:1 into one of three ophthalmic solution treatment groups: SkQ1 1.55 µg/mL, SkQ1 0.155 µg/mL, or 0.0 µg/mL (placebo). Subjects were exposed to a controlled adverse environment chamber at 3 of the 4 study visits (Day −7, Day 1, and Day 29). Investigator assessments occurred at all study visits.
SkQ1 was safe and efficacious in treating dry eye signs and symptoms. Statistically significant improvements with SkQ1 compared to placebo occurred for the dry eye signs of corneal fluorescein staining and lissamine green staining in the central region and lid margin redness, and for the dry eye symptoms of ocular discomfort, dryness, and grittiness. In addition, SkQ1 demonstrated greater efficacy compared to placebo, although the differences were not statistically significant, for corneal fluorescein staining in other regions and/or time points (total staining score, central region, corneal sum score, and temporal region), lissamine green staining for the central and nasal regions, and blink rate scores.
This Phase 2 study indicated that SkQ1 is safe and efficacious for the treatment of dry eye signs and symptoms and supported previous study results.
Avizorex Pharma submits clinical trial application for its lead compound AVX-012 for dry eye syndrome
|Posted by No More Tears on July 6, 2016 at 5:05 AM||comments (0)|
AVIZOREX PHARMA, S.L., an ophthalmology biotech company focused on developing novel therapies for Dry Eye Syndrome, today announced the submission of a Clinical Trial Application (CTA) to the Spanish Competent Authority, requesting clearance to initiate a Phase I/II clinical trial investigating the use of AVX-012 Ophthalmic Solution to treat patients suffering from mild to moderate Dry Eye Syndrome (DES).
The multicenter study, entitled, “Phase I/II, double-blind, placebo-controlled study assessing the safety and efficacy of AVX-012 Ophthalmic Solution in subjects with mild-to-moderate Dry Eye Syndrome”, has been designed to confirm AVX-012 Ophthalmic Solution safety, tolerability and efficacy in DES patients, and if cleared, is expected to be initiated in late 2016 in multiple sites across Spain.
“We believe AVX-012 has the potential to significantly improve both signs and symptoms in this large population of DES patients, due to its selective action on temperature/humidity detecting neurons in the cornea and thereby regulating basal tear production to stabilize tear film and might contribute some analgesic effects that reduce ocular discomfort associated with dry eye”, commented Patrick Tresserras, Chief Executive Officer of Avizorex Pharma, S.L. , who also stated, “Initiation of this trial is another significant milestone in our strategy to create maximum value around the company Dry Eye program”.
About Dry Eye Syndrome (DES)
DES is “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolality of the tear film and inflammation of the ocular surface”. Prevalence reported in the USA, Australia and Europe (Spain) is approximately 5-15 %, 25% in Canada and 30-50% in Asia, with the highest prevalence being observed in subjects of Asian and Hispanic origin (Gayton, 2009; EMA/450332/2012, 2012). DES is more common in women, especially in postmenopausal women, and the prevalence increases with age in both gender (Gayton, 2009).
Treatment of dry eye is mainly symptomatic; very few pharmacological treatments for Dry Eye Syndrome are currently approved in the world. Nowadays, artificial tear preparations are the mainstay of therapy and are generally based on lubricating or viscosity increasing agents. There is no evidence that any type of artificial tear or ocular
lubricant is markedly better than others (Doughty et al., 2009).
Dry Eye therapeutics market will grow to $4.6 Billion by 2024, being one of the fastest growing indications in ophthalmology, while pharmaceutical sales were approximately $2.5 Billion in 2o15, although there are no effective treatment options today available for the millions suffering from Dry Eye Syndrome.
About Avizorex Pharma, S.L.
Avizorex Pharma, S.L. is a Spanish ophthalmology biotech company founded in 2013 in Alicante and backed by Inveready, the seed to early stage Venture Capital Company based in Barcelona. Based in Alicante, Comunitat Valenciana, and with offices in Barcelona Science Park, Avizorex Pharma S.L., is focused on developing novel therapies for Dry Eye Syndrome (DES) based on Prof. Carlos Belmonte’s research on the role of temperaturesensitive
neurons in tear film regulation at the prestigious Alicante Neuroscience Institute.
The company lead product candidate, AVX-012, is a Small Molecule with a novel Mechanism of Action, that is expected to initiate clinical trials by late 2016 to confirm its safety and efficacy in mild to moderate Dry Eye Syndrome patients.
Visit www.avizorex.com for more information.
Dompé, an Italian biopharmaceutical company committed to achieving innovation in the eye disease field, discusses the current knowledge of Dry Eye disease as well as potential therapeutic options.
|Posted by No More Tears on June 25, 2016 at 9:10 AM||comments (0)|
Eye redness and irritation, itchiness and burning of the eye and the sensation of having a foreign body under the eyelid are the most common symptoms of Dry Eye disease, an increasingly common problem associated with environmental, behavioural and lifestyle factors which lead to decreased ocular lubrication.
Dry Eye disease is frequently underestimated but can have significant repercussions on patients’ eyesight, especially in its moderate and severe forms. This is a significant topic for the ophthalmological research community meeting in Barcelona at the 6th EuCornea Congress. The symposium, “Dry Eye disease: from pathogenic mechanism to innovative solutions”, promoted by the biopharmaceutical company Dompé, offers an opportunity to discuss the current landscape with leading international experts, highlight the most recent scientific discoveries into the origin of the condition, as well as reviews future treatment opportunities for the most serious forms of Dry Eye disease.
“Dry Eye disease is a multifactorial condition of the ocular surface and of the tear film that can cause damage to the surface of the eye,”, explains Prof. José Manuel Benítez del Castillo Sánchez della Universidad Complutense de Madrid e Jefe de Sección dell’Hospital Clinico San Carlos. “Tears defend and ensure constant lubrication of the eye. They provide nutrients and keep the eye healthy. A tear film disorder, which can be of a quantitative nature where there is a lack of the liquid component, or of a qualitative nature with a consequent alteration in tear composition, can cause a series of problems that, in the most severe cases, can be difficult to resolve.”.
The state of health of the tear film is essential for guaranteeing not only ocular health, but also good sight.
“It is essential that ophthalmologists are able to use the treatment option that best meet the patient’s needs as, in certain cases, the treatments available do not achieve an adequate response,”, said Prof. Leonardo Mastropasqua, dell'Università degli Studi G. D'Annunzio Chieti Pescara. “An appropriate diagnosis and specific approach must accompany targeted and efficacious therapy.”
Providing a response to the needs of patients with Dry Eye disease is a challenge that Dompé has accepted and is pursuing in the biotechnological research field. “Research into innovative solutions for the unmet needs of patients with Dry Eye disease around the world is a key commitment for Dompé,”, said Eugenio Aringhieri, Chief Executive Officer Dompé. “We are in the final stages of development for lubricin, a glycoprotein naturally present in the body, that we are investigating to determine the tear film protection and recovery mechanism in the treatment of Dry Eye disease. The development of this treatment demonstrates that research can open new therapeutic pathways that have been previously unexplored. We are continuing clinical trials with rhNGF, an investigational molecule of recombinant human Nerve Growth Factor (NGF), currently being evaluated for the treatment of eye diseases such as neurotrophic keratitis and retinitis pigmentosa. Results of an open-label clinical study exploring the compound’s safety and tolerability in patients with Dry Eye disease have recently become available and Dompé will soon initiate a multicentre Phase II study evaluating the safety and efficacy of rhNGF for the treatment of Dry Eye Disease.”
Eye pain sufferers share their experience of living with unrelenting, chronic eye pain and in many cases, extreme light sensitivity.
|Posted by No More Tears on May 29, 2016 at 7:10 AM||comments (0)|
Sylentis Reports Positive Phase II Results With SYL1001 in Treating Ocular Pain Related to Dry Eye Syndrome
|Posted by No More Tears on March 25, 2016 at 4:45 AM||comments (0)|
Sylentis, a pharmaceutical company in the PharmaMar Group (MSE:PHM) and a pioneer in the research and development of new drugs based on gene silencing (interference RNA, RNAi), has presented the results of two Phase II dose-finding and efficacy assessment clinical trials (SYL1001_II and SYL1001_III) with the investigational medicinal product SYL1001 for treating ocular discomfort related to dry eye syndrome.
These randomised parallel group, double-masked and placebo controlled Phase II trials took place at 8 centres in two European countries: Spain and Estonia. A total of 127 patients with ocular pain related to dry eye syndrome took part in the trials, which assessed safety and efficacy of four doses of SYL1001 (0.375%, 0.75%, 1.125% and 2.25%) against placebo following 10 days of once-per-day administration in the form of eye drops.
The results revealed that 1.125% was an optimal dose which achieved the best primary and secondary endpoints, reducing not only ocular pain but also conjunctival hyperaemia related to dry eye syndrome.
The two trials also confirmed a favourable safety and tolerance profile of SYL1001, previously observed in Phase I trial, with no differences in the percentage of adverse events between the assessed doses of SYL1001 and placebo group.
"These positive results support continuing clinical development of SYL1001. Sylentis is currently designing the Phase III clinical program which it will be validated with the relevant regulatory authorities," said Dr Ana Isabel Jiménez, COO of Sylentis.
The results and additional analysis of these clinical trials will be presented at the ARVO conference in May 2016.
SYL1001 is a drug based on RNAi that is administered as preservative-free eye drops; it selectively inhibits production of the TRPV1 receptor. These receptors are ion channels that mediate the transmission of ocular pain. SYL1001 is a small synthetic double-stranded RNA oligonucleotide (siRNA) with a novel and highly selective mechanism of action. Non-clinical studies conducted by Sylentis with SYL1001 have demonstrated it has high ability to inhibit this specific target and block the perception of ocular pain in animals.
SYL1001 is a product undergoing development for the treatment or prevention of ocular pain related to with dry eye syndrome, and has potential to be developed for other pathologies that cause ocular pain (corneal lesions, refractive surgery, etc.)].
About RNA interference (RNAi)
RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space.
Sylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology[vi] with two candidates under development in Phase II studies for glaucoma (bamosiran) and ocular pain (SYL1001). Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at http://www.sylentis.com.
|Posted by No More Tears on September 5, 2015 at 11:45 PM||comments (2)|
BARCELONA — A novel eyelid massaging device improved symptoms of dry eye by enhancing stability and uniformity of the tear lipid layer, according a speaker.
“Eyepeace is designed to express the meibomian glands by a massaging, vertical motion, as a treatment for meibomian gland dysfunction (MGD). It is meant to be used by the patients at home twice a day,” Johnny Moore, MA, FRCOphth, PhD, said at the EuCornea meeting preceding the European Society of Cataract and Refractive Surgeons meeting.